Chronic Hepatitis C virus (HCV) infection causes hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. The factors governing the rate of disease progression along this spectrum of pathology are not known. HCV is highly variable genetically, and genetic variation is a major contributor to virulence in many viral diseases. HCV infection is treated with pegylated interferon ( plus ribavirin, but this fails in half of genotype 1 patients, the most common genotype in the USA. To determine if disease progression in patients who fail therapy can be slowed by long-term use of interferon (, the NIDDK is sponsoring the HALT-C clinical study. Half of these patients are receiving interferon and half are untreated controls. Because of its very large, well-characterized cohort, HALT-C presents a unique opportunity to study how HCV's genetic diversity affects disease progression. Hypothesis: Genetic variation in HCV sequences affecting immune evasion activities modulates the rate of progression of liver disease. Aim 1: Determine how HCV sequence variation is associated with disease progression. HCV induced liver disease is predicted to be influenced by viral sequence variations that modulate virulence through altering the ability to evade host antiviral responses. Therefore, we will sequence the complete HCV ORF in two groups of 20 HALT-C patients and again 3.25 years later employing genetic approaches we developed for the Virahep-C clinical study. Slow Progressors will have minimal disease progression and Rapid Progressors will be patients with major advancement of disease, as defined by the HALT-C endpoints. All patients will be from the untreated arm of HALT-C to assess natural progression of disease. Viral sequences from the groups will be compared to determine if there are viral genetic patterns correlating with disease progression and to characterize viral evolution. Aim 2: Determine how HCV genetic variation affects function of viral proteins implicated in modulating virulence. Variation in viral proteins that affect the ability of HCV to counteract the immune system could modulate the pathogenesis. Therefore, variant viral genes from slow and rapid progressors in which genetic variation correlates with disease progression will be cloned and their biochemical activities proposed to promote virulence will be measured. This study will provide a comprehensive analysis of the role of variation in the HCV coding region on progression of liver disease. This will yield insight into the mechanism of pathology by identifying viral genes associated with differences in disease progression. Finally, these studies may identify viral motifs predictive of rapid disease advancement.